Reproductive and Developmental Toxicity Study of Bromodichloromethane Administered in the Drinking Water to Sprague Dawley Rats

Abstract

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings were not evaluated in accordance with the levels of evidence for reproductive or developmental criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.

The potential toxicity of bromodichloromethane was evaluated using a short-term reproductive and developmental toxicity screen. This study design was selected to identify the physiologic process (development; female reproduction; male reproduction; various somatic organs/processes) that is the most sensitive to bromodichloromethane exposure.

The dose range-finding study was conducted at concentrations of 0, 100, 500, 1000, and 1500 ppm of bromodichloromethane in the drinking water for two weeks. Based on decreases in water consumption, concentrations of 0, 100, 700, and 1300 ppm (Groups 1, 2, 3, and 4, respectively) were selected for the main study. The main study utilized two groups of male rats designated as Group A (non-BrdU treated animals, 10 per group in Groups 1-4) and Group B (BrdU treated, 5 animals in Groups 1, 2, and 3, and 8 animals in Group 4), and three groups of female rats designated as Group A (peri-conception exposure, 10 per group in Groups 1-4), Group B (gestational exposure, 13 per group in Groups 1-4), and Group C (peri-conception exposure, BrdU-treated, 5 animals in Groups 1, 2, and 3, and 8 animals in Group 4). Control animals received deionized water, the vehicle.

During the treatment period, all animals except one survived to the scheduled necropsy. Body weights and feed and water consumption were decreased at many of the intervals for the 700 and 1300 ppm dose groups. Body weights were decreased by 5-13% compared to the controls at many of the intervals while feed consumption was decreased 14-47%, and water consumption was decreased by 17-86% at many of the intervals. The overall calculated mean consumption of BDCM for Groups 2-4 was 11, 53, and 88 mg/kg/day, respectively.

At necropsy, clinical chemistry and hematology endpoints were unaffected by BDCM treatment except for a 43% increase in the 5'-Nucleotidase in the 1300 ppm A males, which most likely represents interference with the secretion of bile, and a 14% decrease in creatinine in the 100 ppm A males.

Necropsy organ weights and organ-to-body weight ratios were comparable to the controls. Gross findings were comparable across all groups. Microscopically, cytoplasmic vacuolization of hepatocytes and individual hepatocyte necrosis were observed in tissues from the 700 and 1300 ppm A males and the 1300 ppm B males, indicative of mild liver damage. Hematopoietic cell proliferation in the spleen was observed in tissues from all dosed A males, but this is most likely an indirect change in response to stress (See Discussion). The Labeling Index for the liver and kidney from the B males were relatively comparable between treated and control groups, but the LI for the liver and kidneys from the 1300 ppm C females were significantly increased, indicating possible early stimulation of cellular proliferation.

There were no treatment-related findings noted in any male and female reproductive parameters.

Results of this study indicate that BDCM at doses at and above 700 ppm produced consistent decreases in body weight and food and water consumption in both sexes, but did not result in any male or female reproductive toxicity. From these data, BDCM is taste-aversive and a general toxicant in both sexes at doses at and above 700 ppm.